The human and animal trypanosomiases have major medical, veterinary, and economic consequences. Leishmaniasis and trypanosomiasis cause chronic and sometimes fatal diseases in people in both developing countries and, as travel to these areas increases, in the developed world as well. In areas of South America where T. cruzi is endemic, heart disease (Chagas)is a signification cause of death and disability. Unfortunately, currently available treatments for all trypanosome infections are expensive, potentially toxic and must be administered for long periods of time. New therapeutic approaches are needed and will require a deeper understanding of the molecular biology of the tgrypanosomatidae.
The aim of the investigator is to develop an increased knowledge of parasite growth in order to pinpoint vulnerable aspects of trypanosome biology, which may prove amenable to newer, more efficacious, and less expensive therapies.
The specific aim of this grant is to further our understanding of the regulatory signals involved in mRNA synthesis in trypanosomes. Virtually nothing is known about the proteins that recruit RNA polymerases to DNA to initiation transcription in these medically important protists. A characteristic genetic trait of all trypanosomes is the ability of every trypanosomal mRNA to acquire a spliced leader (SL) sequence prior to transport from the nucleus. The ubiquitous nature of the spliced leader indicates that this short RNA may be essential in mRNA metabolism. We plan to use established biochemical techniques to explore the structure of proteins that interact with the SL RNA gene promoter and direct SL RNA synthesis. These analyses, which will include gene cloning and protein function studies, will help identify the specific mechanisms that trypanosomes employ to accomplish this fundamental cellular process.
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